Efficacy and safety of inhaled heparin in asthmatic and chronic obstructive pulmonary disease patients: a systematic review and a meta-analysis

Asthma and chronic obstructive pulmonary disease (COPD) are prevalent chronic respiratory disorders that cause significant morbidity and mortality. Some studies evaluated the use of inhaled unfractionated heparin (UFH) in the treatment of asthma and COPD. We aimed to synthesize the available evidence for the efficacy and safety of inhaled heparin in improving lung functions among asthmatic and COPD patients. A comprehensive search was performed using Pubmed, Embase, EBSCO, Scopus, Web of Science, Cochrane CENTRAL, WHO Clinical trials, clinicaltrials.gov, Iranian Clinical trials, Google Scholar, Research Gate, ProQuest Thesis, OVID, and medRxiv databases. Two independent reviewers included all pertinent articles according to PRISMA guidelines, and extract data independently. The two reviewers checked the quality of studies using the ROB2 tool. To determine the pooled effect estimate of the efficacy and safety of inhaled heparin, a meta-analysis was carried out using the R programming language. Publication bias was evaluated using Egger’s regression test. The heterogeneity was explained using a meta-regression, and the quality of evidence was assessed by the GRADE approach. Twenty-six studies with a total of 581 patients were included in the qualitative analysis and 16 in the meta-analysis. The primary outcome was treatment success (improvement of lung function) that was measured by standardized mean differences (SMD) of the forced expiratory volume per second (FEV1) either per ml or percentage. Heparin has a large effect on both FEV1% and FEV1 ml when compared to the control group (SMD 2.7, 95% CI 1.00; 4.39; GRADE high, SMD 2.12, 95% CI − 1.49; 5.72: GRADE moderate, respectively). Secondary outcomes are other lung functions improving parameters such as PC20 (SMD 0.91, 95% CI − 0.15; 1.96). Meta-regression and subgroup analysis show that heparin type, dose, year of publication, study design, and quality of studies had a substantial effect. Regarding safety, inhaled heparin showed a good coagulation profile and mild tolerable side effects. Inhaled heparin showed improvement in lung functions either alone or when added to standard care. More large parallel RCTs are needed including COPD patients, children, and other types, and stages of asthmatic patients.

-No history of ischemic heart disease, pulmonary bleeding (within the previous three months), bleeding diathesis.
-No allergy to heparin, or history of heparin-induced thrombocytopenia (HIT).
Every 6 hours for fourteen days.
Device: nebulization chamber (Ameco Technology; particle size: 0.5-10 μm, nebulization rate: > 0.3 ml/min) connected to the inspiratory limb of the breathing circuit 15 cm from the Y of the circuit.      Selection process 8 Specify the methods used to decide whether a study met the inclusion criteria of the review, including how many reviewers screened each record and each report retrieved, whether they worked independently, and if applicable, details of automation tools used in the process.

P6
Data collection process 9 Specify the methods used to collect data from reports, including how many reviewers collected data from each report, whether they worked independently, any processes for obtaining or confirming data from study investigators, and if applicable, details of automation tools used in the process.

P6
Data items 10a List and define all outcomes for which data were sought. Specify whether all results that were compatible with each outcome domain in each study were sought (e.g. for all measures, time points, analyses), and if not, the methods used to decide which results to collect.

P6
10b List and define all other variables for which data were sought (e.g. participant and intervention characteristics, funding sources). Describe any assumptions made about any missing or unclear information.

P6
Study risk of bias assessment 11 Specify the methods used to assess risk of bias in the included studies, including details of the tool(s) used, how many reviewers assessed each study and whether they worked independently, and if applicable, details of automation tools used in the process.

P7
Effect 12 Specify for each outcome the effect measure(s) (e.g. risk ratio, mean difference) used in the synthesis or presentation of P7p7 Synthesis methods 13a Describe the processes used to decide which studies were eligible for each synthesis (e.g. tabulating the study intervention characteristics and comparing against the planned groups for each synthesis (item #5)).

P7
13b Describe any methods required to prepare the data for presentation or synthesis, such as handling of missing summary statistics, or data conversions.

P7
13c Describe any methods used to tabulate or visually display results of individual studies and syntheses. P7 13d Describe any methods used to synthesize results and provide a rationale for the choice(s). If meta-analysis was performed, describe the model(s), method(s) to identify the presence and extent of statistical heterogeneity, and software package(s) used.

P7
13e Describe any methods used to explore possible causes of heterogeneity among study results (e.g. subgroup analysis, meta-regression).

P7
13f Describe any sensitivity analyses conducted to assess robustness of the synthesized results. P8 Reporting bias assessment 14 Describe any methods used to assess risk of bias due to missing results in a synthesis (arising from reporting biases). P7 Certainty assessment 15 Describe any methods used to assess certainty (or confidence) in the body of evidence for an outcome. P8

Study selection
16a Describe the results of the search and selection process, from the number of records identified in the search to the number of studies included in the review, ideally using a flow diagram.

P9, P26
16b Cite studies that might appear to meet the inclusion criteria, but which were excluded, and explain why they were excluded.

P 23-25
Study characteristics 17 Cite each included study and present its characteristics. P 23-25 Risk of bias in studies 18 Present assessments of risk of bias for each included study. P9, P27

Results of individual studies
19 For all outcomes, present, for each study: (a) summary statistics for each group (where appropriate) and (b) an effect estimate and its precision (e.g. confidence/credible interval), ideally using structured tables or plots.

P27-28 Appendix 2
Results of syntheses 20a For each synthesis, briefly summarise the characteristics and risk of bias among contributing studies. P 9-13 20b Present results of all statistical syntheses conducted. If meta-analysis was done, present for each the summary estimate and its precision (e.g. confidence/credible interval) and measures of statistical heterogeneity. If comparing groups, describe the direction of the effect. 20d Present results of all sensitivity analyses conducted to assess the robustness of the synthesized results. P 9-13 Reporting biases 21 Present assessments of risk of bias due to missing results (arising from reporting biases) for each synthesis assessed. P13, appendix 2 Certainty of evidence 22 Present assessments of certainty (or confidence) in the body of evidence for each outcome assessed.

DISCUSSION
Discussion 23a Provide a general interpretation of the results in the context of other evidence. P14 23b Discuss any limitations of the evidence included in the review. P15 23c Discuss any limitations of the review processes used. P15 23d Discuss implications of the results for practice, policy, and future research. P15

OTHER INFORMATION
Registration and protocol 24a Provide registration information for the review, including register name and registration number, or state that the review was not registered.
P4 24b Indicate where the review protocol can be accessed, or state that a protocol was not prepared. P4 24c Describe and explain any amendments to information provided at registration or in the protocol. P4 Support 25 Describe sources of financial or non-financial support for the review, and the role of the funders or sponsors in the review. P15 Competing interests 26 Declare any competing interests of review authors. P15 Availability of data, code and other materials 27 Report which of the following are publicly available and where they can be found: template data collection forms; data extracted from included studies; data used for all analyses; analytic code; any other materials used in the review. For more information, visit: http://www.prisma-statement.org/